A variety of dosage forms have been used for drugs that require long-term administration. To reduce the number of doses that need to be given, and to provide a stable level of the drug in the body, these drugs are preferably given in a sustained-release formulation. One type of sustained-release drug formulation that has been used is biodegradable microspheres containing drug trapped inside the microsphere. One such product is LUPRON Depot, which is biodegradable microspheres containing leutinizing hormone-releasing hormone (leuprolide or LHRH). Leuprolide is used for the treatment of hormone-dependent cancers, particularly prostate cancer, and precocious puberty.
Microparticles are particles with a diameter of approximately 1 to 1000 microns. For injection purposes, microparticles smaller than 125 microns are preferred. Microparticles of this size can be injected with a standard hypodermic needle, instead of surgically implanted. One type of microparticle is composed of a network of a biodegradable polymer that entraps a drug. As the polymer biodegrades in the body, the drug is released. The most commonly used biodegrabable polymers are polylactic acid and a copolymer of lactic acid and glycolic acid.
The most widely used methods to prepare biodegrabable microparticles are phase separation, spray drying, and solvent evaporation. Phase separation, also known as coacervation, uses a decrease of the polymer solubility by the addition of a non-solvent. In a typical procedure, biodegradable polymer is dissolved in an organic solvent (e.g., dichloromethane). Lipophilic drugs are dissolved in the polymer solution. Hydrophilic drugs are dissolved in water and then dispersed in the polymer solution (water in oil (w/o) emulsion) or dispersed as a solid powder. A non-solvent (typically silicon oil) is gradually added. Two phases form: a polymer-rich silicon oil phase and a polymer-depleted liquid organic solvent phase. As the organic solvent is extracted or evaporates, polymer microparticles with entrapped drug solidify in the silicon oil phase. The coacervate (silicon oil) adsorbs to the polymer microparticles.
In spray drying, the biodegradable polymer is dissolved in volatile organic solvent, such as dichloromethane. The drug is dissolved or dispersed in the polymer solution. The solution or dispersion is sprayed in heated air. The solvent evaporates, resulting in the formation of solid microparticles.
Solvent evaporation is the most commonly used method of preparing microparticles. In this method a drug-containing organic polymer solution is emulsified into a dispersion medium that is typically aqueous but may be oil. The methods can be further classified into oil in water (o/w), water in oil in water (w/o/w), and oil in oil (o/o) emulsion methods.
In an o/w method, drug and polymer are dissolved in an organic solvent, such as dichloromethane or a methanol/dichloromethane mixture. The drug-polymer-organic solvent solution is dispersed in an aqueous phase. An emulsifier, typically poly(vinyl alcohol), is included in the aqueous phase to help form small organic solvent droplets in the aqueous phase. The organic solvent evaporates with stirring, and with the evaporation, the droplets solidify into polymer microparticles with entrapped drug.
In a w/o/w double emulsion, an aqueous drug solution is prepared and dispersed into a solution of the polymer in an organic solvent to form a water-in-oil emulsion containing the drug and polymer. The w/o polymer-drug emulsion is then emulsified into an aqueous phase to form a w/o/w emulsion. With stirring, the organic solvent evaporates, allowing the polymer-drug droplets in the emulsion to solidify into microparticles.
In an o/o emulsion method, drug and polymer are dissolved in a water-miscible solvent (e.g., acetonitrile). That solution is emulsified into an oily phase in the presence of an emulsifier such as SPAN 80 to form an oil-in-oil emulsion. The organic solvent is extracted by the oil and microparticles can be harvested by filtration.
Prior art methods of forming biodegradable polymer drug-containing microparticles have some disadvantages. Emulsifier or oil can adhere to the microparticles and contaminate them. Some methods are difficult to scale up.
New methods of forming biodegradable drug-containing microparticles are needed.